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    <head><title>Fats and degeneration</title></head>
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        <h1>
            Fats and degeneration
        </h1>

        <p>
            <hr />
            <hr />
            <hr />
        </p>
        <p>
            <strong>50 years ago, in the first phase of marketing the polyunsaturated fatty acids (PUFA), linoleic acid
                was "heart protective," and the saturated fats raised cholesterol and caused heart disease.</strong>
        </p>
        <p>
            <strong>In the second phase, the other "essential fatty acid," linolenic acid, was said to be even better
                than linoleic acid.</strong>
        </p>
        <p>
            <strong>In the third phase, the longer chain omega -3 (omega minus three, or n minus three) fatty acids, DHA
                and EPA, are said to be even better than linolenic acid.</strong>
        </p>
        <p>
            <strong>Along the way, the highly unsaturated arachidonic acid, which we and other animals make out of the
                linoleic acid in foods, was coming to be identified with the "harmful animal fats." But we just didn't
                hear much about how the amount of arachidonic acid in the tissues depended on the amount of linoleic
                acid in the diet.</strong>
        </p>

        <p>
            <strong>U.S. marketing dominates the world economy, including of course the communication media, so we
                shouldn't expect to hear much about the role of PUFA in causing cancer, diabetes, obesity, aging,
                thrombosis, arthritis and immunodeficiency, or to hear about the benefits of the saturated fats.
            </strong>
        </p>
        <p>
            <strong>The saturated fats include the "tropical fats," because they are synthesized in very warm organisms,
                and are very stable at those temperatures. Their stability offers some protection against the unstable
                PUFA.
            </strong>
        </p>
        <p>
            <strong>Several of the degenerative conditions produced by the "essential fatty acids" can be reversed by
                use of saturated fats, varying in length from the short chains of coconut oil to the very long chains of
                waxes.</strong>
        </p>
        <p>
            <hr />
            <hr />
            <hr />
        </p>
        <p>
            When a person uses a drug, there is generally an awareness that the benefit has to be weighed against the
            side effects. But if something is treated as a "nutrient," especially an "essential nutrient," there is an
            implication that it won't produce undesirable side effects.
        </p>
        <p>
            Over the last thirty years I have asked several prominent oil researchers what the evidence is that there is
            such a thing as an "essential fatty acid." One professor cited a single publication about a solitary sick
            person who recovered from some sickness after being given some unsaturated fat. (If he had known of any
            better evidence, wouldn't he have mentioned it?) The others (if they answered at all) cited "Burr and Burr,
            1929." The surprising thing about that answer is that these people can consider any nutritional research
            from 1929 to be definitive. It's very much like quoting a 1929 opinion of a physicist regarding the
            procedure for making a hydrogen bomb. What was known about nutrition in 1929? Most of the B vitamins weren't
            even suspected, and it had been only two or three years since "vitamin B" had been subdivided into two
            factors, the "antineuritic factor," B<sub>1</sub>, and the "growth factor," B<sub>2</sub>. Burr had no way
            of really understanding what deficiencies or toxicities were present in his experimental diet.
        </p>

        <p>
            A few years after the first experiments, Burr put one of his "essential fatty acid deficient" rats under a
            bell jar to measure its metabolic rate, and found that the deficient animals were metabolizing 50% faster
            than rats that were given linoleic and linolenic acids as part of their diet. That was an important
            observation, but Burr didn't understand its implications. Later, many experiments showed that the
            polyunsaturated fats slowed metabolism by profoundly interfering with the function of the thyroid hormone
            and the cellular respiratory apparatus. Without the toxic fats, respiratory energy metabolism was very
            intense, and a diet that was nutritionally sufficient for a sluggish animal wouldn't necessarily be adequate
            for the vigorous animals.
        </p>
        <p>
            Several publications between 1936 and 1944 made it very clear that Burr's basic animal diet was deficient in
            various nutrients, especially vitamin B<sub>6</sub>. <strong>
                The disease that appeared in Burr's animals could be cured by fat free B-vitamin preparations, or by
                purified vitamin B6 when it became available.</strong>
            <strong>
                A zinc deficiency produces similar symptoms,
            </strong>

            and at the time Burr did his experiments, there was no information on the effects of fats on mineral
            absorption. If a diet is barely adequate in the essential minerals, increasing the metabolic rate, or
            decreasing intestinal absorption of minerals, will produce mineral deficiencies and metabolic problems.
        </p>
        <p>
            Although "Burr's disease" clearly turned out to be a B-vitamin deficiency, probably combined with a mineral
            deficiency, it continues to be cited as the basis justifying the multibillion dollar industry that has grown
            up around the "essential" oils.
        </p>
        <p>
            Two years before Burr's experiment, German researchers found that a fat-free diet prevented almost all
            spontaneous cancers in rats. Later work showed that the polyunsaturated fats both initiate and promote
            cancer. With that knowledge, the people who kept claiming that "linoleic, linolenic, and maybe arachidonic
            acid are the essential fatty acids," should have devoted some effort to finding out how much of that
            "essential nutrient" was enough, so that people could minimize their consumption of the carcinogenic stuff.
        </p>
        <p>
            Between the first and second world wars, cod liver oil was recommended as a vitamin supplement, at first as
            a source of vitamin A, and later as a source of vitamins A and D. But in the late 1940s, experimenters used
            it as the main fat in dogs' diet, and found that they all died from cancer, while the dogs on a standard
            diet had only a 5% cancer mortality. That sort of information, and the availability of synthetic vitamins,
            led to the decreased use of cod liver oil.
        </p>
        <p>
            But around that time, the seed oil industry was in crisis because the use of those oils in paints and
            plastics was being displaced by new compounds made from petroleum. The industry needed new markets, and
            discovered ways to convince the public that seed oils were better than animal fats. They were called the
            "heart protective oils," though human studies soon showed the same results that the animal studies had,
            namely, that they were toxic to the heart and increased the incidence of cancer.
        </p>

        <p>
            The "lipid hypothesis" of heart disease argued that cholesterol in the blood caused atherosclerosis, and
            that the polyunsaturated oils lowered the amount of cholesterol in the blood. Leaving behind the concept of
            nutritional essentiality, this allowed the industry (and their academic supporters, such as Frederick Stare
            at Harvard) to begin promoting the oils as having drug-like therapeutic properties. Larger amounts of
            polyunsaturated fat were supposed to be more protective by lowering the cholesterol, and were to be
            substituted for the saturated fats, which supposedly raised cholesterol and increased heart disease,
            producing atherosclerotic plaques in the blood vessels and increasing the formation of blood clots.
        </p>
        <p>
            Since all ordinary foods contain significant amounts of the polyunsaturated fats, there was no reason to
            think that, even if they were essential nutrients, people were likely to become deficient in them. So the
            idea of treating the seed oils as drug-like substances, to be taken in large amounts, appealed to the food
            oil industry.
        </p>
        <p>
            Prostaglandins, which are produced in the body by oxidizing the polyunsaturated fatty acids, provided an
            opportunity for the drug industry to get involved in a new market, and<strong>
                the prostaglandins offered a new way of arguing for the nutritional essentiality of linoleic and related
                acids: A whole system of "hormones" is made from these molecules.</strong> Since some of the
            prostaglandins suppress immunity, cause inflammation and promote cancer growth, some people have divided
            them into the "good prostaglandins" and the "bad prostaglandins."
        </p>
        <p>
            PGI2, or prostacyclin, is considered to be a good prostaglandin, because it causes vasodilatation, and so
            drug companies have made their own synthetic equivalents: Epoprostenol, iloprost, taprostene, ciprostene,
            UT-15, beraprost, and cicaprost. Some of these are being investigated for possible use in killing cancer.
        </p>

        <p>
            But many very useful drugs that already existed, including cortisol and aspirin, were found to achieve some
            of their most important effects by inhibiting the formation of the prostaglandins. It was the body's load of
            polyunsaturated fats which made it very susceptible to inflammation, stress, trauma, infection, radiation,
            hormone imbalance, and other fundamental problems, and drugs like aspirin and cortisone, which limit the
            activation of the stored "essential fatty acids," gain their remarkable range of beneficial effects partly
            by the restraint they impose on those stored toxins.
        </p>
        <p>
            Increasingly, the liberation of arachidonic acid from tissues during stress is seen as a central factor in
            all forms of stress, either acute (as in burns or exercise) or chronic (as in diabetes or aging). And, as
            the fat stores become more toxic, it seems that they more readily liberate the free fatty acids. (For
            example, see Iritani, et al., 1984)
        </p>
        <p>
            During this same period, a few experimenters were finding that animals which were fed a diet lacking the
            "essential" fatty acids had some remarkable properties<strong>:</strong> They consumed oxygen and calories
            at a very high rate, their mitochondria were unusually tough and stable, their tissues could be transplanted
            into other animals without provoking immunological rejection, and they were very hard to kill by trauma and
            a wide variety of toxins that easily provoke lethal shock in animals on the usual diet. As the Germans had
            seen in 1927, they had a low susceptibility to cancer, and new studies were showing that they weren't
            susceptible to various fibrotic conditions, including alcoholic liver cirrhosis.
        </p>
        <p>
            In 1967 a major nutrition publication, <em>Present Knowledge in Nutrition,</em>

            published Hartroft and Porta's observation that the "age pigment," lipofuscin, was formed in proportion to
            the amount of polyunsaturated fat and oxidants in the diet. The new interest in organ transplantation led to
            the discovery that the polyunsaturated fats prolonged graft survival, by suppressing the immune system.
            Immunosuppression was considered to have a role in the carcinogenicity of the "essential" fatty acids.
        </p>
        <p>
            Around the same time, there were studies that showed that unsaturated fats retarded brain development and
            produced obesity.
        </p>
        <p>
            Substances very much like the prostaglandins, called isoprostanes and neuroprostanes, are formed
            spontaneously from highly unsaturated fatty acids, and are useful as indicators of the rate of lipid
            peroxidation in the body. Most of the products of lipid peroxidation are toxic, as a result of their
            reactions with proteins, DNA, and the mitochondria. The age-related glycation products that are usually
            blamed on sugar, are largely the result of peroxidation of the polyunsaturated fatty acids.
        </p>
        <p>
            Through the 1970s, this sort of information about the harmful effects of the PUFA was being slowly
            assimilated by the culture, though many dietitians still spoke of "the essential fatty acids, vitamin F." By
            1980, it looked as though responsible researchers would see the promotion of cancer, heart disease,
            mitochondrial damage, hypothyroidism and immunosuppression caused by the polyunsaturated fats as their most
            important feature, and would see that there had never been a basis for believing that they were essential
            nutrients.
        </p>
        <p>
            But then, without acknowledging that there had been a problem with the doctrine of essentiality, fat
            researchers just started changing the subject, shifting the public discourse to safer, more profitable
            topics. The fats that had been called essential, but that had so many toxic effects, were no longer
            emphasized, and the failed idea of "essentiality" was shifted to different categories of polyunsaturated
            fats.
        </p>
        <p>
            The addition of the long chain highly unsaturated fats to baby food formulas was recently approved, on the
            basis of their supposed "essentiality for brain development." One of the newer arguments for the
            essentiality of the PUFA is that "they are needed for making cell membranes." But human cells can grow and
            divide in artificial culture solutions which contain none of the polyunsaturated fats, and no one has
            claimed that they are growing "without membranes."
        </p>

        <p>
            The long chain fats found in fish and some algae don't interfere with animal enzymes as strongly as the seed
            oils do, and so by comparison, they aren't so harmful. They are also so unstable that relatively little of
            them is stored in the tissues. (And when they are used as food additives, it's necessary to use antioxidants
            to keep them from becoming smelly and acutely toxic.)
        </p>
        <p>
            When meat is grilled at a high temperature, the normally spaced double bonds in PUFA migrate towards each
            other, becoming more stable, so that linoleic acid is turned into "conjugated linoleic acid." This analog of
            the "essential" linoleic acid competes against the linoleic acid in tissues, and protects against cancer,
            atherosclerosis, inflammation and other effects of the normal PUFA. Presumably, anything which interferes
            with the essential fatty acids is protective, when the organism contains dangerous amounts of PUFA. Even the
            trans-isomers of the unsaturated fatty acids (found in butterfat, and convertible into conjugated linoleic
            acid) can be protective against cancer.
        </p>
        <p>
            In the 1980s the oil promoters were becoming more sophisticated, and were publishing many experiments in
            which the fish oils were compared with corn oil, or safflower, or soy oil, and in many of those experiments,
            the animals' health was better when they didn't eat the very toxic seed oils, that contained the "essential
            fatty acids," linoleic and linoleic acids.
        </p>
        <p>
            Besides comparing the fish oils to the stronger toxins, another trick is to take advantage of the same
            immunosuppressive property that had seemed troublesome, and to emphasize their ability to temporarily
            alleviate some autoimmune or allergic diseases. X-rays were once used that way, to treat arthritis and
            ringworm, for example.
        </p>

        <p>
            And, knowing that cancer cells have the ability to consume large amounts of fatty acids, they would test
            these fats in tissue culture dishes, and demonstrate that they were poisonous, cytotoxic, to the fast
            growing cancer cells. Although they caused cancer in animals, if they could be shown to kill cancer cells in
            a dish, they could be sold as anticancer drugs/nutrients, with the special mystique of being "essential
            fatty acids." Strangely, their ability to kill cancer cells under some circumstances and to suppress some
            immunological reactions is being promoted in close association with the doctrine that these fats are
            nutritionally essential.
        </p>
        <p>
            Arachidonic acid is made from linoleic acid, and so those two oils were considered as roughly equivalent in
            their ability to meet our nutritional needs, but a large part of current research is devoted to showing the
            details of how fish oils protect against arachidonic acid. The "balance" between the omega -3 and the omega
            -6 fatty acids is increasingly being presented as a defense against the toxic omega -6 fats. But the
            accumulation of unsaturated fats with aging makes any defense increasingly difficult, and the extreme
            instability of the highly unsaturated omega -3 fats creates additional problems.
        </p>
        <p>
            PUFA and x-rays have many biological effects in common. They are immunosuppressive, but they produce their
            own inflammatory reactions, starting with increased permeability of capillaries, disturbed coagulation and
            proteolysis, and producing fibrosis and tumefaction or tissue atrophy. This isn't just a coincidence, since
            ionizing radiation attacks the highly unstable polyunsaturated molecules, simply accelerating processes that
            ordinarily happen more slowly as a result of stress and aging.
        </p>
        <p>
            Prolonged stress eventually tends to be a self-sustaining process, impairing the efficient respiratory
            production of energy, converting muscle tissue to amino acids, suppressing the thyroid, and activating
            further mobilization of fatty acids. Fatty acids are mobilized from within the structure of cells by
            phospholipases, and from fat tissues by other lipases.
        </p>
        <p>
            The highly unsaturated fatty acids, as well as the ordinary "essential fatty acids," act directly to
            increase capillary permeability, even without conversion into prostaglandins, and they interfere in many
            ways with the clotting and clot removal systems. The effects of PUFA taken in a meal probably disturb the
            clotting system more than the same quantity of saturated fat, contrary to many of the older publications.
            The PUFA are widely believed to prevent clotting, but when cod liver oil is given to "EFA deficient"
            animals, it activates the formation of clots (Hornstra, et al., 1989). An opposite effect is seen when a
            long chain fatty acid synergizes with aspirin, to restrain clotting (Molina, et al., 2003).
        </p>
        <p>
            Fibrosis is a generalized consequence of the abnormal capillary permeability produced by things that disrupt
            the clotting system. Estrogen, with its known contribution to the formation of blood clots and edema and
            fibrosis and tumors, achieves part of its effect by maintaining a chronically high level of free fatty
            acids, preferentially liberating arachidonic acid, rather than saturated fatty acids.
        </p>

        <p>
            Butter, beef fat, and lamb fat are the only mostly saturated fats produced on a large scale in the U.S., and
            the cheapness/profitability of the seed oils made it easy to displace them. But, in the face of the immense
            amount of propagandistic "health" claims that have been made against the saturated fats, it's instructive to
            look at some of their actual effects, especially on the clotting system, and the related fibrotic reactions.
        </p>
        <p>
            The saturated fatty acids are very unreactive chemically. Coconut oil, despite containing about 1% of the
            unstable PUFA, can be left in a bucket at room temperature for a year or more without showing any evidence
            of deterioration, suggesting that the predominance of saturated fat acts as an antioxidant for the
            unsaturated molecules. In the body, the saturated fats seem to act the same way, preventing or even
            reversing many of the conditions caused by oxidation of fats.
        </p>
        <p>
            The stress-induced liberation of arachidonic acid causes blood vessels to leak, and this allows fibrin to
            escape from the blood stream, into the basement membrane and beyond into the extracellular matrix, where it
            produces fibrosis. (Cancer, autoimmune diseases, and heart disease involve the same inflammatory,
            thrombotic, fibrotic processes as the nominal fibroses.) Scleroderma, liver cirrhosis, fibrosis of the
            lungs, heart, and other organs, and all the diseases in which fibrous tissue becomes dense and progressively
            contracts, involve similar processes, and the treatments which are successful are those that stop the
            inflammation produced by the oxidation of the polyunsaturated fatty acids.
        </p>
        <p>
            Retroperitoneal fibrosis is now known to be produced by estrogen, and is treated by antiestrogenic and
            antiserotonergic drugs, but as early as 1940 Alejandro Lipschutz demonstrated that chronic exposure to very
            low doses of estrogen produced fibromas in essentially every part of the body. Earlier, Loeb had studied the
            action of large doses of estrogen, which produced fibrosis of the uterus, as if it had accelerated aging.
            Following Lipschutz' work, in which he demonstrated the "antifibromatogenic" actions of pregnenolone and
            progesterone, several Argentine researchers showed that progesterone prevented and cured abdominal adhesions
            and other fibrotic conditions, including retroperitoneal fibrosis.
        </p>
        <p>
            Since estrogen produces both leakiness of the capillaries and excessive formation of fibrin, its effects
            will be seen first in the organs where it concentrates, but eventually anywhere capillaries leak fibrin.
            Estrogen activates the phospholipase which liberates arachidonic acid, and progesterone inhibits that
            phospholipase.
        </p>

        <p>
            As the fat tissues become more burdened with arachidonic acid, they release it more easily in response to
            moderately lipolytic stress signals. This could explain the increased levels of free fatty acids and lipid
            peroxidation that occur with aging. In animals that are "deficient" in the polyunsaturated fatty acids,
            adrenalin doesn't have the lipolytic effect that it does in animals on the standard diet. With aging, there
            is not only a tendency to have chronically higher free fatty acids in the blood, but for those fatty acids
            to be more unsaturated. The phospholipids of mitochondria and microsomes become more unsaturated with aging
            (Laganiere and Yu, 1993, Lee, et al., 1999). In the human retina there is a similar accumulation of PUFA
            with aging (Nourooz-Zadeh and Pereira, 1999), which implies that the aged retina will be more easily damaged
            by light.
        </p>
        <p>
            Several studies suggest that a high degree of unsaturation in the fats is fundamentally related to the aging
            process, since long lived species have a lower degree of unsaturation in their fats. Caloric restriction
            decreases the age-related accumulation of the fatty acids with 4 and 5 double bonds.
        </p>
        <p>
            Although publicity has emphasized the anti-inflammatory effects of fish oil, experiments show that it is
            extremely effective in producing alcohol-related liver cirrhosis. Breakdown products of polyunsaturated fats
            (isoprostanes and 4-HNE) are found in the blood of people with alcoholic liver disease (Aleynik, et al.,
            1998). In the absence of polyunsaturated fats, alcohol doesn't produce cirrhosis. Saturated fats allow the
            fibrosis to regress<strong>:</strong>
        </p>
        <p>
            <strong>"A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis,
                inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated
                fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation...."
                (Nanji, et al., 1995, 2001)</strong>
        </p>
        <p>
            In these studies, the animals were switched from fish oil to either palm oil or medium chain triglycerides
            (a major fraction of coconut oil). In other studies, Knittel, et al. (1995), show that fibrinogen, in "a
            clotting-like process," is involved in the development of liver fibrosis, and that this appears to provide a
            basis for the growth of additional extracellular matrix.
        </p>

        <p>
            Brown, et al. (1989), discussed this developmental process (leaky capillaries, fibrosis) in relation to
            wound healing, lung disease, and tumor growth.
        </p>
        <p>
            The relatively few studies of fish oil and linoleic acid that compare them with palmitic acid or coconut oil
            have produced some very important results. For example, pigs exposed to endotoxin developed severe lung
            problems (resembling "shock lung") when they had been on a diet with either fish oil or Intralipid (which is
            mostly linoleic acid, used for intravenous feeding in hospitals), but not after palmitic acid (Wolfe, et
            al., 2002).
        </p>
        <p>
            Eating low-fat seafood (sole, whitefish, turbot, scallops, oysters, lobster, shrimp, squid, etc.) once in a
            while can provide useful trace minerals, without much risk. However, fish from some parts of the ocean
            contain industrial contaminants in the fat, and large fish such as tuna, swordfish, Chilean sea bass and
            halibut contain toxic amounts of mercury in the muscles. Chilean sea bass (Patagonian toothfish) is very
            high in fat, too.
        </p>
        <p>
            About ten years ago I met a young man with a degenerative brain disease, and was interested in the fact that
            he (working on a fishing boat) had been eating almost a pound of salmon per day for several years. There is
            now enough information regarding the neurotoxic effects of fish oil to justify avoidance of the fatty fish.
        </p>
        <p>
            Some of the current advertising is promoting fish oil to prevent cancer, so it's important to remember that
            there are many studies showing that it increases cancer.
        </p>
        <p>
            The developmental and physiological significance of the type of fatty acid in the diet has been established
            for a long time, but cultural stereotypes and commercial interests are threatened by it, so it can't be
            discussed publicly.
        </p>

        <p>REFERENCES</p>
        <p>
            Alcohol Clin Exp Res 1998 Feb;22(1):192-6.<strong>
                Increased circulating products of lipid peroxidation in patients with alcoholic liver disease.</strong>
            Aleynik SI, Leo MA, Aleynik MK, Lieber CS
        </p>
        <p>
            Ann N Y Acad Sci. 1976;275:28-46. <strong>Metabolic influences in experimental thrombosis.</strong>
            Antoniades HN, Westmoreland N.
        </p>

        <p>
            Nutr Cancer. 2001;41(1-2):91-7.<strong>
                Vaccenic acid feeding increases tissue levels of conjugated linoleic acid and suppresses development of
                premalignant lesions in rat mammary gland.</strong> Banni S, Angioni E, Murru E, Carta G, Melis MP,
            Bauman D, Dong Y, Ip C.
        </p>
        <p>
            Obstet Gynecol. 1987 Sep;70(3 Pt 2):502-4. <strong>The treatment of retroperitoneal fibromatosis with
                medroxyprogesterone acetate.</strong> Barnhill D, Hoskins W, Burke T, Weiser E, Heller P, Park R. Wide
            excision is the recommended primary therapy for retroperitoneal fibromatosis. Radiation therapy and a
            variety of medications have been used to treat patients with recurrent tumors, but the response to these
            agents has not been uniform. The patient presented was successfully treated with medroxyprogesterone acetate
            for recurrent retroperitoneal fibromatosis that was refractory to multiple operative resections and
            radiation therapy.
        </p>
        <p>
            Medicina (B Aires). 1978 Mar-Apr;38(2):215-6. <strong>[Fibromatosis, relaxin and progesterone]</strong> [in
            Spanish] Barousse AP. [Letter]
        </p>

        <p>
            Medicina (B Aires). 1985;45(2):159-63.<strong>
                Progesterone as therapy for retroperitoneal fibrosis.</strong> Bilder CR, Barousse AP, Mazure PA.
        </p>
        <p>
            Adv Exp Med Biol. 1976;75:497-503. <strong>Effect of ionizing radiation on liver microcirculation and
                oxygenation.</strong> Bicher HI, Dalrymple GV, Ashbrook D, Smith R, Harris D.
        </p>
        <p>
            Lipids. 1981 May;16(5):323-7. <strong>Iodination of docosahexaenoic acid by lactoperoxidase and thyroid
                gland in vitro: formation of an lodolactone.</strong>
            Boeynaems JM, Watson JT, Oates JA, Hubbard WC. "In the presence of iodide, hydrogen peroxide and
            lactoperoxidase, docosahexaenoic acid (22:6 omega 3) was converted into iodinated compounds."
        </p>
        <p>
            Am Rev Respir Dis 1989 Oct;140(4):1104-7.<strong>
                Leaky vessels, fibrin deposition, and fibrosis: a sequence of events common to solid tumors and to many
                other types of disease.</strong> Brown LF, Dvorak AM, Dvorak HF
        </p>
        <p>
            Medicina (B Aires). 1979 Sep-Oct;39(5):652-4.<strong>
                [Effect of progesterone in the treatment of a patient with idiopathic retroperitoneal fibrosis]</strong>
            [in Spanish] Casadei DH, Najun Zarazaga C, Leanza HJ, Schiappapietra JH.
        </p>
        <p>
            Biochem Mol Biol Int 1993 Jan;29(1):175-83.<strong>
                Influence of antioxidant vitamins on fatty acid inhibition of lymphocyte proliferation.</strong> Calder
            PC, Newsholme EA. "Vitamin E (10 microM) increased human lymphocyte proliferation by 35%. However, vitamin E
            did not prevent the inhibitory effects of fatty acids upon lymphocyte proliferation. It is concluded that
            inhibition of lymphocyte proliferation by fatty acids is not caused by their conversion to peroxidised
            products."
        </p>

        <p>
            Clin Sci (Lond). 1992 Jun;82(6):695-700.<strong>
                Polyunsaturated fatty acids suppress human peripheral blood lymphocyte proliferation and interleukin-2
                production.</strong> Calder PC, Newsholme EA.
        </p>
        <p>
            J Neurochem 1980 Oct;35(4):1004-7. <strong>
                Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling.</strong
            > Chan PH, Fishman RA
        </p>
        <p>
            Int J Cancer 2001 Mar 15;91(6):894-9. <strong>Tumor invasiveness and liver metastasis of colon cancer cells
                correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor,
                etodolac.</strong> Chen WS, Wei SJ, Liu JM, Hsiao M, Kou-Lin J, Yang WK.
        </p>

        <p>
            Free Radic Biol Med. 1999 Jul;27(1-2):51-9. <strong>Arachidonic acid interaction with the mitochondrial
                electron transport chain promotes reactive oxygen species generation.</strong> Cocco T, Di Paola M, Papa
            S, Lorusso M.
        </p>
        <p>
            Clin Exp Metastasis 1997 Jul;15(4):410-7. <strong>Influence of lipid diets on the number of metastases and
                ganglioside content of H59 variant tumors.</strong> Coulombe J, Pelletier G, Tremblay P, Mercier G, Oth
            D.
        </p>
        <p>
            BJU Int. 2003 Jun;91(9):830-8. <strong>Fibrin as an inducer of fibrosis in the tunica albuginea of the rat:
                a new animal model of Peyronie's disease.</strong>

            Davila HH, Ferrini MG, Rajfer J, Gonzalez-Cadavid NF.
        </p>
        <p>
            Carcinogenesis 1994 Jul;15(7):1399-404. <strong>Peroxidation of linoleic, arachidonic and oleic acid in
                relation to the induction of oxidative DNA damage and cytogenetic effects.</strong> de Kok TM, ten
            Vaarwerk F, Zwingman I, van Maanen JM, Kleinjans JC.
        </p>
        <p>
            Biochem Biophys Res Commun. 2000 Oct 14;277(1):128-33. <strong>Arachidonic acid causes cytochrome c release
                from heart mitochondria.</strong> Di Paola M, Cocco T, Lorusso M.
        </p>

        <p>
            J Physiol. 1998 Mar 1;507 ( Pt 2):541-7. <strong>Arachidonic acid increases cerebral microvascular
                permeability by free radicals in single pial microvessels of the anaesthetized rat.
            </strong>
            Easton AS, Fraser PA.
        </p>
        <p>
            Am J Physiol. 1992 May;262(5 Pt 1):E637-43. ATP depletion stimulates calcium-dependent protein breakdown in
            chick skeletal Muscle. Fagan JM, Wajnberg EF, Culbert L, Waxman L.
        </p>
        <p></p>
        <p>
            Cancer Res 1998 Aug 1;58(15):3312-9. <strong>Dietary omega-3 polyunsaturated fatty acids promote colon
                carcinoma metastasis in rat liver.</strong> Griffini P, Fehres O, Klieverik L, Vogels IM, Tigchelaar W,
            Smorenburg SM, Van Noorden CJ.
        </p>

        <p>
            J Indian Med Assoc 1997 Mar;95(3):67-9, 83.<strong>
                Association of dietary ghee intake with coronary heart disease and risk factor prevalence in rural
                males.
            </strong>
            Gupta R, Prakash H
        </p>
        <p>
            Transplantation 1995 Sep 27;60(6):570-7. <strong>The effect of dietary polyunsaturated fatty acids (PUFA) on
                acute rejection and cardiac allograft blood flow in rats.</strong> Haw MP, Linnebjerg H, Chavali SR,
            Forse RA. "The immunosuppressive effect of dietary PUFA warrants further investigation, and their use as a
            possible adjunctive treatment in organ transplantation should be considered."
        </p>
        <p>
            Dtsch Med Wochenschr. 2003 Jun 20;128(25-26):1395-8. <strong>[Rare cause of chronic abdominal pain:
                retractile mesenteritis]</strong> [in German] Hermann F, Speich R, Schneemann M. "Retractile
            mesenteritis is a rare cause of chronic abdominal pain with variable symptoms. Its aetiology is unknown. In
            case of bowel ischemia a surgical approach is preferred, milder forms may be treated with immunosuppressive
            agents as well as oral progesterone. Progesterone has exhibited positive effects on fatty tissue with
            successful treatment in desmoid tumors and retroperitoneal fibrosis. Here in we could demonstrate its safe
            and efficient use in a patient with retractile mesenteritis."
        </p>

        <p>
            Mech Ageing Dev 2001 Apr 15;122(4):427-43. <strong>Effect of the degree of fatty acid unsaturation of rat
                heart mitochondria on their rates of H2O2 production and lipid and protein oxidative damage.</strong>
            Herrero A, Portero-Otin M, Bellmunt MJ, Pamplona R, Barja G. "Previous comparative studies have shown that
            long-lived animals have lower fatty acid double bond content in their mitochondrial membranes than
            short-lived ones. In order to ascertain whether this trait protects mitochondria by decreasing lipid and
            protein oxidation and oxygen radical generation, the double bond content of rat heart mitochondrial
            membranes was manipulated by chronic feeding with semi-purified AIN-93G diets rich in highly unsaturated
            (UNSAT) or saturated (SAT) oils. UNSAT rat heart mitochondria had significantly higher double bond content
            and lipid peroxidation than SAT mitochondria. They also showed increased levels of the markers of protein
            oxidative damage malondialdehyde-lysine, protein carbonyls, and N(e)-(carboxymethyl)lysine adducts." "These
            results demonstrate that increasing the degree of fatty acid unsaturation of heart mitochondria increases
            oxidative damage to their lipids and proteins, and can also increase their rates of mitochondrial oxygen
            radical generation in situations in which the degree of reduction of Complex III is higher than normal.
            These observations strengthen the notion that the relatively low double bond content of the membranes of
            long-lived animals could have evolved to protect them from oxidative damage."
        </p>
        <p>
            Biochem J. 1994 May 15;300 ( Pt 1):251-5. <strong>Regulation of fibrinolysis by non-esterified fatty
                acids.</strong> Higazi AA, Aziza R, Samara AA, Mayer M. "<strong>Examination of the fatty acid
                specificity showed that a minimal chain length of 16 carbon atoms and the presence of at least one
                double bond, preferably in a cis configuration, were required for inhibition of the fibrinolytic
                activity of plasmin."
            </strong>
        </p>
        <p>
            Science. 1976 Feb 27;191(4229):861-2. <strong>Nicotinic acid reduction of plasma volume loss after thermal
                trauma.</strong> Hilton JG, Wells CH. Intravenous administration of nicotinic acid to the anesthetized
            dog prior to thermal trauma reduced plasma loss at 10 minutes after burn from 7 milliliters per kilogram to
            less than 2 millimeters per kilogram. During the next 50 minutes plasma loss was the same in treated and
            untreated animals. An additional dose of nicotinic acid 30 minutes after burn prevented this further loss.
        </p>

        <p>
            Z Gesamte Inn Med. 1976 Oct 15;31(20):838-43. <strong>[Age-dependence of catecholamine effects in man. IV.
                Effects of specific inhibitors on the lipolytic action of alpha and beta adrenergics]</strong> [in
            German] Hoffmann H.
        </p>
        <p>
            Neurochem Res. 2000 Feb;25(2):269-76. <strong>Cortical impact injury in rats promotes a rapid and sustained
                increase in polyunsaturated free fatty acids and diacylglycerols.</strong> Homayoun P, Parkins NE,
            Soblosky J, Carey ME, Rodriguez de Turco EB, Bazan NG.<strong> </strong>"At day one, free 22:6 and 22:6-DAGs
            showed the greatest increase (590% and 230%, respectively). These results suggest that TBI elicits the
            hydrolysis of phospholipids enriched in excitable membranes, targeting early on 20:4-phospholipids (by 30
            min post- trauma) and followed 24 hours later by<strong>
                preferential hydrolysis of DHA-phospholipids. These lipid metabolic changes may contribute to the
                initiation and maturation of neuronal and fiber track degeneration observed following cortical impact
                injury."</strong>
        </p>
        <p>
            Thromb Res. 1989 Jan 1;53(1):45-53. <strong>Normalization by dietary cod-liver oil of reduced thrombogenesis
                in essential fatty acid deficient rats.</strong>
            Hornstra G, Haddeman E, Don JA.
        </p>
        <p>
            Radiographics. 2003 Nov-Dec;23(6):1561-7. <strong>CT Findings in Sclerosing Mesenteritis (Panniculitis):
                Spectrum of Disease.</strong> Horton KM, Lawler LP, Fishman EK.
        </p>
        <p>
            Nutr Cancer. 1985;7(4):199-209. <strong>Isomeric fatty acids and tumorigenesis: a commentary on recent
                work.</strong> Hunter JE, Ip C, Hollenbach EJ. "Neither epidemiological nor experimental studies
            published to date have demonstrated any valid association between trans fatty acid ingestion and
            tumorigenesis. A recent study showed that under controlled conditions, a fat with a high content of trans
            fatty acids did not promote the development of mammary tumors induced in rats by
            7,12-dimethylbenz[a]anthracene to any greater extent than did a comparable fat with a high content of cis
            fatty acids. In addition, in this<strong>
                study a high trans fat was less tumor promoting than was a blend of fats that simulated the dietary fat
                composition of the United States and had a lower level of trans fatty acids.</strong>"
        </p>

        <p>
            Medicina (B Aires). 1978 Mar-Apr;38(2):215. <strong>[Progesterone and retroperitoneal fibrosis]</strong> [in
            Spanish] Introzzi A.[Letter]
        </p>
        <p>
            Cancer Res. 1985 May;45(5):1997-2001. <strong>Requirement of essential fatty acid for mammary tumorigenesis
                in the rat.</strong> Ip C, Carter CA, Ip MM. "<strong>Mammary tumorigenesis was very sensitive to
                linoleate intake and increased proportionately in the range of 0.5 to 4.4% of dietary
                linoleate."</strong>
        </p>
        <p>
            Biochim Biophys Acta. 1984 Nov 6;802(1):17-23.<strong>
                Activation of bovine platelets induced by long-chain unsaturated fatty acids at just below their lytic
                concentrations, and its mechanism.</strong> Kitagawa S, Endo J, Kametani F.
        </p>

        <p>
            Clin Exp Metastasis 2000;18(5):371-7. <strong>Promotion of colon cancer metastases in rat liver by fish oil
                diet is not due to reduced stroma formation.</strong>
            Klieveri L, Fehres O, Griffini P, Van Noorden CJ, Frederiks WM. <strong>
                "Recently, it was demonstrated that dietary omega-3 polyunsaturated fatty acids (PUFAs) induce 10-fold
                more metastases in number and 1000-fold in volume in an animal model of colon cancer metastasis in rat
                liver."</strong>
        </p>
        <p>
            Folia Haematol Int Mag Klin Morphol Blutforsch. 1977;104(1):1-10. <strong>[Review: hemorrhagic diathesis
                resulting from acute exposure to ionizing Radiation]</strong>
            [Article in German] Krantz S, Lober M. The symptoms of the acute radiopathy are chiefly characterized by a
            severe blood coagulation disorder. The main results and problems of research work on this haemorrhagic
            diathesis are shortly reviewed.
        </p>
        <p>
            Prostaglandins. 1978 Apr;15(4):557-64. <strong>Prostaglandin I2 as a potentiator of acute inflammation in
                rats.</strong> Komoriya K, Ohmori H, Azuma A, Kurozumi S, Hashimoto Y, Nicolaou KC, Barnette WE, Magolda
            RL.
        </p>
        <p>
            Gerontology 1993;39(1):7-18. <strong>Modulation of membrane phospholipid fatty acid composition by age and
                food restriction.</strong> Laganiere S, Yu BP. H.M. "Phospholipids from liver mitochondrial and
            microsomal membrane preparations were analyzed to further assess the effects of age and lifelong calorie
            restriction on membrane lipid composition." <strong>"The data revealed characteristic patterns of
                age-related changes in ad libitum (AL) fed rats:</strong>
            <strong>
                membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively, while
                membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately 40%, and
                22:5 content almost doubled making the peroxidizability index increase with age.</strong>" "<strong>We
                concluded that the membrane-stabilizing action of long-term calorie restriction relates to the selective
                modification of membrane long-chain polyunsaturated fatty acids during aging.</strong>"
        </p>
        <p>
            Medicina (B Aires). 1978 Mar-Apr;38(2):123-32. <strong>[Effective treatment of several types of fibromatosis
                with progesterone. Fibrous mediastinitis, desmoid tumors, paraneoplastic fibrosis]</strong> [in Spanish]
            Lanari A, Molinas FC, Castro Rios M, Paz RA.
        </p>

        <p>
            Medicina (B Aires). 1979 Nov-Dec;39(6):826-35. <strong>[Progesterone in fibromatosis and
                atherosclerosis]</strong> [in Spanish] Lanari A.
        </p>
        <p>
            Free Radic Biol Med 1999 Feb;26(3-4):260-5. <strong>Modulation of cardiac mitochondrial membrane fluidity by
                age and calorie intake.</strong> Lee J, Yu BP, Herlihy JT. <strong>"The fatty acid composition of the
                mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty
                acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the
                differences."</strong> "Considered together, these results suggest that DR <strong>maintains the
                integrity of the cardiac mitochondrial membrane fluidity by minimizing membrane damage through
                modulation of membrane fatty acid profile."</strong>
        </p>
        <p>
            Lipids 2001 Jun;36(6):589-93. <strong>
                Effect of dietary restriction on age-related increase of liver susceptibility to peroxidation in
                rats.</strong> Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK.
        </p>
        <p>
            Acta Chir Scand. 1976;142(1):20-5. <strong>Induction of endogenous fibrinolysis inhibition in the dog.
                Effect of intravascular coagulation and release of free fatty acids.</strong> Lindquist O, Bagge L,
            Saldeen T. "In all groups subjected to infusion of thrombin an increase in plasma free fatty acids (FFA) was
            observed. The role of this increase for the development <strong>
                of fibrinolysis inhibition was tested by infusion of norepinephrine alone and in combination with
                nicotinic acid. Norepinephrine caused an increase of FFA after 2 hours and in urokinase inhibitor
                activity after 24-48 hours.</strong> Both of these were diminished by high doses of nicotinic acid,
            indicating that the release of FFA rather than intravascular coagulation might be the principal mechanism
            underlying the occurrence of fibrinolysis inhibition following trauma."
        </p>

        <p>
            Proc Natl Acad Sci U S A 1990 Nov;87(22):8845-9. <strong>Incorporation of marine lipids into mitochondrial
                membranes increases susceptibility to damage by calcium and reactive oxygen species: evidence for
                enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty acids.</strong>
            Malis CD, Weber PC, Leaf A, Bonventre JV.
        </p>
        <p>
            Prostaglandins Leukot Essent Fatty Acids 1994 Jul;51(1):33-40.<strong>
                Suppression of human T-cell growth in vitro by cis-unsaturated fatty acids: relationship to free
                radicals and lipid peroxidation.</strong> Madhavi N, Das UN, Prabha PS, Kumar GS, Koratkar R, Sagar PS.
        </p>
        <p>
            Clin Exp Metastasis 1998 Jul;16(5):407-14.<strong>
                Diminution of the development of experimental metastases produced by murine metastatic lines in
                essential fatty acid-deficient host mice.</strong> Mannini A, Calorini L, Mugnai G, Ruggieri S.
        </p>
        <p>
            Biochem Pharmacol. 1990 Mar 1;39(5):879-89. <strong>Histamine release from rat mast cells induced by
                metabolic activation of polyunsaturated fatty acids into free radicals.</strong> Masini E, Palmerani B,
            Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF.
        </p>
        <p>
            Journal of Lipid Research, Vol. 44, 271-279, February 2003. <strong>Arachidonic acid and prostacyclin
                signaling promote adipose tissue development : a human health concern?</strong>
            F. Massiera, P. Saint-Marc, J. Seydoux , T. Murata , T. Kobayashi , S. Narumiya , P. Guesnet, Ez-Zoubir
            Amri, R. Negrel and G. Ailhaud1.
        </p>
        <p>
            Infection. 1994 Mar-Apr;22(2):106-12. <strong>Influence of dietary (n-3)-polyunsaturated fatty acids on
                leukotriene B4 and prostaglandin E2 synthesis and course of experimental tuberculosis in guinea
                pigs.</strong> Mayatepek E, Paul K, Leichsenring M, Pfisterer M, Wagner D, Domann M, Sonntag HG, Bremer
            HJ.
        </p>

        <p>
            Biochim Biophys Acta 1994 Sep 15;1214(2):209-20. <strong>Reinvestigation of lipid peroxidation of linolenic
                acid.</strong> Mlakar A, Spiteller G. "Thus, a great number of previously unknown lipid peroxidation
            products was detected. It is assumed that these compounds also occur--at least as intermediates--in lipid
            peroxidation processes in mammalian tissue."
        </p>
        <p>
            Prostaglandins Leukot Essent Fatty Acids. 2003 May;68(5):305-10. <strong>Synergistic effect of D-003 and
                aspirin on experimental thrombosis models.</strong> Molina V, Arruzazabala ML, Carbajal D, Mas R.
        </p>
        <p>
            Chem Res Toxicol. 2001 Apr;14(4):431-7. <strong>Defining mechanisms of toxicity for linoleic acid
                monoepoxides and diols in Sf-21 cells.</strong> Moran JH, Mon T, Hendrickson TL, Mitchell LA, Grant DF.
        </p>

        <p>
            J Biochem (Tokyo). 1977 Aug;82(2):529-33. <strong>Effects of free fatty acids on fibrinolytic
                activity.</strong> Muraoka T, Okuda H. A novel method for the estimation of fibrinolytic activity is
            proposed. In this method, a fibrin clot suspension is used as a substrate (fibrin is known to be a
            physiological substrate of plasmin). The fibrin clot suspension was prepared by homogenization of human
            fibrin clots. With this method, we found that free fatty<strong>
                acids inhibited the plasmin activity, and long-chain, unsaturated free fatty acids had a particularly
                strong inhibitory action on plasmin. As regards the mechanism of the inhibitory action, free fatty acids
                may not inhibit complex formation between plasmin and fibirin, but may make it impossible for plasmin to
                act on fibrin due to deformation of the surface of the fibrin clot.</strong>
        </p>
        <p>
            Alcohol Clin Exp Res. 1986 Jun;10(3):271-3. <strong>Dietary factors and alcoholic cirrhosis.</strong> Nanji
            AA, French SW.
        </p>
        <p>
            Gastroenterology. 1995 Aug;109(2):547-54. <strong>Dietary saturated fatty acids: a novel treatment for
                alcoholic liver disease.
            </strong>

            Nanji AA, Sadrzadeh SM, Yang EK, Fogt F, Meydani M, Dannenberg AJ.
        </p>
        <p>
            J Pharmacol Exp Ther. 1996 Jun;277(3):1694-700. <strong>Medium chain triglycerides and vitamin E reduce the
                severity of established experimental alcoholic liver disease.</strong> Nanji AA, Yang EK, Fogt F,
            Sadrzadeh SM, Dannenberg AJ.
        </p>
        <p>
            Hepatology. 1997 Dec;26(6):1538-45.<strong>
                Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse
                fibrosis in alcohol-induced liver disease in the rat.</strong> Nanji AA, Zakim D, Rahemtulla A, Daly T,
            Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.
        </p>

        <p>
            J Pharmacol Exp Ther. 2001 Nov;299(2):638-44. <strong>
                Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued
                ethanol administration.</strong> Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ.
        </p>
        <p>
            Gastroenterology 1995 Apr;108(4):1124-35.<strong>
                Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver
                injury.</strong>
            Neubauer K, Knittel T, Armbrust T, Ramadori G "<strong>Fibrinogen/fibrin deposition in damaged livers was
                studied by immunohistology."
            </strong>
            "Immunohistology showed striking amounts of fibrinogen and fibrin deposits in pericentral necrotic areas
            (short-term damage) and within fibrotic septa (long-term damage)." "The results show fibrinogen/fibrin
            deposition during short-term liver injury and liver fibrogenesis, which may suggest the involvement of a
            "clotting-like process" in short-term liver damage and liver fibrosis. The data might indicate that
            fibrin/fibronectin constitute a "provisional matrix," which affects the attraction and proliferation of
            inflammatory and matrix-producing cells."
        </p>
        <p>
            Ophthalmic Res. 1999;31(4):273-9. <strong>Age-related accumulation of free polyunsaturated fatty acids in
                human retina.</strong> Nourooz-Zadeh J, Pereira P.
        </p>
        <p>
            Chem Res Toxicol. 2002 Mar;15(3):367-72. <strong>Formation of cyclic deoxyguanosine adducts from omega-3 and
                omega-6 polyunsaturated fatty acids under oxidative conditions.</strong> Pan J, Chung FL.
        </p>
        <p>
            Radiobiologiia. 1985 Nov-Dec;25(6):763-7. <strong>[Mechanism of circulatory disorders in animals irradiated
                at high doses]</strong> [in Russian] Pozharisskaia TD, Vasil'eva TP, Sokolova EN, Alekseeva II. Some
            data are reported on pathoanatomical changes, a status of the microcirculatory channel and the coagulogram
            of animals affected by high doses of ionizing radiation. <strong>The signs of disseminated intravascular
                blood coagulation have been revealed.</strong>
        </p>
        <p>
            J Biol Chem. 1998 May 29;273(22):13605-12. <strong>Formation of isoprostane-like compounds (neuroprostanes)
                in vivo from docosahexaenoic acid.</strong> Roberts LJ 2nd, Montine TJ, Markesbery WR, Tapper AR, Hardy
            P, Chemtob S, Dettbarn WD, Morrow JD.
        </p>
        <p>
            Nutr Cancer 1995;24(1):33-45.<strong>
                Effects of linoleic acid and gamma-linolenic acid on the growth and metastasis of a human breast cancer
                cell line in nude mice and on its growth and invasive capacity in vitro.</strong> Rose DP, Connolly JM,
            Liu XH
        </p>
        <p>
            Arch Toxicol. 1997;71(9):563-74.<strong>
                Impaired cellular immune response in rats exposed perinatally to Baltic Sea herring oil or
                2,3,7,8-TCDD.</strong>

            Ross PS, de Swart RL, van der Vliet H, Willemsen L, de Klerk A, van Amerongen G, Groen J, Brouwer A,
            Schipholt I, Morse DC, van Loveren H, Osterhaus AD, Vos JG.
        </p>
        <p>
            Nutr Cancer 1998;30(2):137-43. <strong>
                Effects of dietary n-3-to-n-6 polyunsaturated fatty acid ratio on mammary carcinogenesis in rats.
            </strong>Sasaki T, Kobayashi Y, Shimizu J, Wada M, In'nami S, Kanke Y, Takita T. "An increase in the n-3/n-6
            ratio did not suppress the incidence or reduce the latency of mammary tumor development. <strong>
                The number and weight of mammary tumors per tumor-bearing rat tended to be large in the group with an
                n-3/n-6 ratio of 7.84 compared with those in the other groups. As the n-3/n-6 ratios were elevated, the
                total number and weight of tumors increased gradually.</strong>"
        </p>
        <p>
            J. Biol. Chem. 1940 132: 539-551.<strong> Essential fatty acids, vitamin B</strong>
            <sub><strong>6</strong></sub>
            <strong>, and other factors in the cure of rat acrodynia</strong>. H. Schneider, H. Steenbock, and Blanche
            R. Platz
        </p>

        <p>
            Science. 1988 May 20;240(4855):1032-3. <strong>Essential fatty acid depletion of renal allografts and
                prevention of rejection.</strong> Schreiner GF, Flye W, Brunt E, Korber K, Lefkowith JB.
        </p>
        <p>
            Physiol Bohemoslov. 1990;39(2):125-34.<strong>
                Proportion of individual fatty acids in the non-esterified (free) fatty acid (FFA) fraction in the serum
                of laboratory rats of different ages.</strong> Smidova L, Base J, Mourek J, Cechova I.
        </p>
        <p>
            Placenta. 2003 Nov;24(10):965-73. <strong>Augmented PLA(2)Activity in Pre-eclamptic Decidual Tissue-A Key
                Player in the Pathophysiology of 'Acute Atherosis' in Pre-eclampsia?</strong> Staff AC, Ranheim T,
            Halvorsen B.
        </p>
        <p>
            Acta Neurochir Suppl (Wien) 1994;60:20-3<strong>. Mechanisms of glial swelling by arachidonic acid.</strong>
            Staub F, Winkler A, Peters J, Kempski O, Baethmann A.
        </p>
        <p>
            Arch Biochem Biophys. 1991 Aug 15;289(1):33-8. <strong>A possible mechanism of mitochondrial dysfunction
                during cerebral ischemia: inhibition of mitochondrial respiration activity by arachidonic acid.
            </strong>
            Takeuchi Y, Morii H, Tamura M, Hayaishi O, Watanabe Y.
        </p>
        <p>
            J Drug Target. 2003 Jan;11(1):45-52.<strong>
                Modulation of tumor-selective vascular blood flow and extravasation by the stable prostaglandin 12
                analogue beraprost sodium.</strong> Tanaka S, Akaike T, Wu J, Fang J, Sawa T, Ogawa M, Beppu T, Maeda H.
        </p>
        <p>
            Am J Clin Nutr. 2003 May;77(5):1125-32. <strong>Effect of individual dietary fatty acids on postprandial
                activation of blood coagulation factor VII and fibrinolysis in healthy young men.</strong> Tholstrup T,
            Miller GJ, Bysted A, Sandstrom B.
        </p>
        <p>
            Biochem Soc Trans. 2003 Oct;31(Pt 5):1075-9. <strong>Regression of pre-established atherosclerosis in the
                apoE-/- mouse by conjugated linoleic acid.</strong>

            Toomey S, Roche H, Fitzgerald D, Belton O.
        </p>
        <p>
            Int J Biochem Cell Biol. 2003 May;35(5):749-55. <strong>Increased muscle proteasome activities in rats fed a
                polyunsaturated fatty acid supplemented diet.</strong> Vigouroux S, Farout L, Clavel S, Briand Y, Briand
            M. "Changes in the proteasome system, a dominant actor in protein degradation in eukaryotic cells, have been
            documented in a large number of physiological and pathological conditions." "With the polyunsaturated fatty
            acid enriched diet, the chymotrypsin-like and peptidylglutamylpeptide hydrolase activities increased by 45%
            in soleus and extensor digitorum longus (EDL), and by 90% in the gastrocnemius medialis (GM) muscle.
            Trypsin-like activity of the proteasome increased by 250% in soleus, EDL and GM." "Proteasome activities and
            level were less stimulated with a monounsaturated fatty acid supplemented diet." "Unsaturated fatty acids
            are particularly prone to free radical attack. Thus, we suggest that alterations in muscle proteasome may
            result from monounsaturated and polyunsaturated fatty acid-induced peroxidation, in order to eliminate
            damaged proteins."
        </p>
        <p>
            J Am Coll Nutr. 2000 Aug;19(4):478S-486S. <strong>Conjugated linoleic acid and bone biology.</strong>
            Watkins BA, Seifert MF. "Recent investigations with<strong> </strong>growing rats given butter fat and
            supplements of CLA demonstrated an increased rate of bone formation and reduced ex vivo bone PGE2
            production, respectively."
        </p>

        <p>
            Ups J Med Sci. 1979;84(3):195-201. <strong>Effect of nicotinic acid on the posttraumatic increase in free
                fatty acids and fibrinolysis inhibition activity in the rat.</strong> Wegener T, Bagge L, Saldeen T.
            Nicotinic acid effectively inhibited the posttraumatic increase in both free fatty acids (FFA) and
            fibrinolysis inhibition activity (FIA) in the blood in rats, indicating that FFA might be involved in the
            posttraumatic increase of FIA. The FIA in the liver was greater than that in other organs studied and was
            increased in the posttraumatic phase. The possible role of the liver in the posttraumatic increase of FIA is
            discussed.
        </p>
        <p>
            Am J Physiol Regul Integr Comp Physiol. 2001 Mar;280(3):R908-12. <strong>CLA reduces antigen-induced
                histamine and PGE(2) release from sensitized guinea pig tracheae.</strong> Whigham LD, Cook EB, Stahl
            JL, Saban R, Bjorling DE, Pariza MW, Cook ME.
        </p>
        <p>
            Toxicol Appl Pharmacol 1993 May;120(1):72-9.<strong>
                Essential fatty acid deficiency in cultured human keratinocytes attenuates toxicity due to lipid
                peroxidation.</strong>

            Wey HE, Pyron L, Woolery M.
        </p>
        <p>
            Nutrition. 2002 Jul-Aug;18(7-8):647-53. <strong>Dietary fat composition alters pulmonary function in
                pigs.</strong> Wolfe RR, Martini WZ, Irtun O, Hawkins HK, Barrow RE. © Ray Peat Ph.D. 2009. All Rights
            Reserved. www.RayPeat.com
        </p>
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